Podocyte as the Target for Aldosterone

Abstract

Abstract-Accumulating evidence suggests that mineralocorticoid receptor blockade effectively reduces proteinuria in hypertensive patients. However, the mechanism of the antiproteinuric effect remains elusive. In this study, we investigated the effects of aldosterone on podocyte, a key player of the glomerular filtration barrier. Uninephrectomized rats were continuously infused with aldosterone and fed a high-salt diet. Aldosterone induced proteinuria progressively, associated with blood pressure elevation. Notably, gene expressions of podocyte-associated molecules nephrin and podocin were markedly decreased in aldosterone-infused rats at 2 weeks, with a gradual decrease thereafter. Immunohistochemical studies and electron microscopy confirmed the podocyte damage. Podocyte injury was accompanied by renal reduced nicotinamide-adenine dinucleotide phosphate oxidase activation, increased oxidative stress, and enhanced expression of aldosterone effector kinase Sgk1. Treatment with eplerenone, a selective aldosterone receptor blocker, almost completely prevented podocyte damage and proteinuria, with normalization of elevated reduced nicotinamide-adenine dinucleotide phosphate oxidase activity. In addition, proteinuria, podocyte damage, and Sgk1 upregulation were significantly alleviated by tempol, a membrane-permeable superoxide dismutase, suggesting the pathogenic role of oxidative stress. Although hydralazine treatment almost normalized blood pressure, it failed to improve proteinuria and podocyte damage. In cultured podocytes with consistent expression of mineralocorticoid receptor, aldosterone stimulated membrane translocation of reduced nicotinamide-adenine dinucleotide phosphate oxidase cytosolic components and oxidative stress generation in podocytes. Furthermore, aldosterone enhanced the expression of Sgk1, which was inhibited by mineralocorticoid receptor antagonist and tempol. In conclusion, podocytes are injured at the early stage in aldosterone-infused rats, resulting in the occurrence of proteinuria. Aldosterone can directly modulate podocyte function, possibly through the induction of oxidative stress and Sgk1.

Mitochondrial Dysfunction Mediates Aldosterone-Induced Podocyte Damage

“…9,31 Further evidence suggests a role of oxidative stress in the pathogenesis of podocyte injury in Aldo-infused rats. 3 However, the source of Aldo-induced oxidative stress in podocytes is still poorly characterized. Mitochondria are important cellular organelles for the energy production pathway, oxidative phosphorylation that is associated with the generation of the by-product superoxide anion (O 2 .…”

“…Given the recent evidence for involvement of ROS in the podocyte injury, 3,26,27 we first tested whether ROS mediate Aldo-induced down-regulation of nephrin. 2=,7= dichlorfluorescein (DCF) fluorescence, an index of ROS production, was significantly increased after 60 minutes of Aldo treatment, and this increase was prevented by rosiglitazone treatment (Figure 3, A-C).…”

“…Moreover, exogenous infusion of Aldo reverses the renoprotective effects of angiotensin-converting enzyme inhibitors in hypertensive remnant kidney rats, and in stroke-prone, spontaneously hypertensive rats. 2 In vitro studies show that Aldo exerts a direct deleterious influence on kidney cells, including podocytes, [3][4][5] mesangial cells, proximal tubular epithelial cells, 6 and fibroblasts. In particular, Aldo causes podocyte injury in vivo and in vitro, and Aldo blockade is therapeutic in renal injury.…”

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

“…30 Angiotensin type 1 receptors are expressed on mesangial cells 19,24,31 and podocytes 26,28,32 and mineralocorticoid receptors are also expressed by both cell types. 29,33,34 The likely importance of the local glomerular RAAS relates to the pathogenesis of glomeruloscleorsis and the loss of glomerular permselectivity observed in many glomerular diseases. In cultured mesangial cells, Ang II [35][36][37] and aldosterone 38,39 provoke synthesis of extracellular matrix (ECM) proteins that accumulate in glomerulosclerosis.…”

“…44 Aldosterone can also damage podocytes by inducing apoptosis and reducing nephrin gene expression. 30,33,45 Thus, through autocrine or endocrine mechanisms, Ang II and aldosterone may induce damage and/or pro-fibrotic pathways in mesangial cells or podocytes, and thus contribute to glomerular damage.…”